chr3-124563062-A-T

Variant names:

• chr3-124563062-A-T
• rs145432562
• NM_001388419.1:c.5155A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001388419.1(KALRN):​c.5155A>T​(p.Met1719Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000823 in 1,215,464 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.2e-7 (0 hom.)
• Consequence: KALRN NM_001388419.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.32
• Publications: 0 publications found

Genes affected

KALRN (HGNC:4814): (kalirin RhoGEF kinase) Huntington's disease (HD), a neurodegenerative disorder characterized by loss of striatal neurons, is caused by an expansion of a polyglutamine tract in the HD protein huntingtin. This gene encodes a protein that interacts with the huntingtin-associated protein 1, which is a huntingtin binding protein that may function in vesicle trafficking. [provided by RefSeq, Apr 2016]

LOC105374076 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001388419.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KALRN	NM_001388419.1	MANE Select	c.5155A>T	p.Met1719Leu	missense	Exon 34 of 60	NP_001375348.1
	KALRN	NM_001024660.5		c.5149A>T	p.Met1717Leu	missense	Exon 34 of 60	NP_001019831.2
	KALRN	NM_001322988.2		c.5149A>T	p.Met1717Leu	missense	Exon 34 of 49	NP_001309917.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KALRN	ENST00000682506.1	MANE Select	c.5155A>T	p.Met1719Leu	missense	Exon 34 of 60	ENSP00000508359.1
	KALRN	ENST00000360013.7	TSL:5	c.5149A>T	p.Met1717Leu	missense	Exon 34 of 60	ENSP00000353109.3
	KALRN	ENST00000354186.8	TSL:5	c.5053A>T	p.Met1685Leu	missense	Exon 33 of 59	ENSP00000346122.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.23e-7 AC: 1 AN: 1215464 Hom.: 0 Cov.: 30 AF XY: 0.00000166 AC XY: 1 AN XY: 602386

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26300

American (AMR) AF: 0.00 AC: 0 AN: 37288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16896

East Asian (EAS) AF: 0.00 AC: 0 AN: 16806

South Asian (SAS) AF: 0.00 AC: 0 AN: 83218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32492

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4474

European-Non Finnish (NFE) AF: 0.00000105 AC: 1 AN: 953964

Other (OTH) AF: 0.00 AC: 0 AN: 44026

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.019	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-0.83	T
PhyloP100		9.3
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.30
Sift	Benign	0.036	D
Sift4G	Benign	0.19	T
Vest4		0.66
MutPred		0.24		Loss of catalytic residue at M1717 (P = 5e-04)
MVP		0.90
ClinPred		0.96	D
GERP RS		4.4
Mutation Taster		=63/37	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs145432562; hg19: chr3-124281909;